Nasal delivery

ABSTRACT

A delivery device for and method of delivering a dose of substance for systemic uptake to a nasal cavity of a subject. The delivery device includes a nosepiece unit for insertion into a nasal cavity of a subject and an outlet unit which includes at least one nozzle for delivering substance for systemic uptake substantially only to surfaces in one or both of the anterior region and an anterior section of the posterior region of the nasal cavity of the subject. The delivery device also includes a substance supply unit which is operable to deliver a dose of substance to the at least one nozzle.

This application is a continuation of U.S. patent application Ser. No.15/001,344, filed Jan. 20, 2016, which is a divisional of U.S. patentapplication Ser. No. 12/293,972, filed Aug. 27, 2009, now U.S. Pat. No.9,272,104, which is a National Phase Application of InternationalApplication No. PCT/IB07/001998, filed on Mar. 23, 2007, which claimsthe benefit of and priority to Application No, GB 0605799,6, filed onMar. 23, 2006. The disclosure of each of the above applications isincorporated herein by reference in its entirety.

The present invention relates to a nasal delivery device for and amethod of intranasally delivering substances for systemic uptake, asliquids, such as suspensions or solutions, and powders, where containingmedicaments, typically pharmaceuticals, or vaccines.

Referring to FIG. 1(a), the nasal airway 1 comprises the two nasalcavities separated by the nasal septum, which airway 1 includes numerousostia, such as the paranasal sinus ostia 3 and the tubal ostia 5, andolfactory cells, and is lined by nasal mucosa. The nasal airway 1 cancommunicate with the nasopharynx 7, the oral cavity 9 and the lowerairway 11, with the nasal airway 1 being in selective communication withthe anterior region of the nasopharynx 7 and the oral cavity 9 byopening and closing of the oropharyngeal velum 13. The velum 13, whichis often referred to as the soft palate, is illustrated in solid line inthe closed position, as achieved by providing a certain positivepressure in the oral cavity 9, such as achieved on exhalation throughthe oral cavity 9, and in clashed line in the open position.

The nasal cavities each comprise a posterior region which is that regionwhich is posterior of the nasal valve NV and an anterior region which isthat region which is anterior of the nasal valve NV, as illustrated inFIG. 1(b).

The nasal valve NV comprises the anterior bony cavum which containsinferior turbinate erectile tissue and septal erectile tissue, which aresupported respectively by compliant ala tissue and the rigidcartilaginous septum [Cole]. These elements combine to form a dynamicvalve, which extends over several millimetres, that adjusts nasalairflow, and is stabilized by cartilage and hone, modulated by voluntarymuscle and regulated by erectile tissue. The lumen of the nasal valve NVis the section of narrowest cross-sectional area between the posteriorand anterior regions of the nasal airway, and is much longer andnarrower dorsally than ventrally, and this lumen defines a triangularentrance which extends to the piriform region of the bony cavum. Thenasal valve NV is lined in its anterior part with transitionalepithelium, with a gradual transition posterior to respiratoryepithelium. The nasal valve NV and anterior vestibule define roughly theanterior one-third of the nose.

The posterior region of the nasal airway is that region which is linedwith respiratory epithelium, which is ciliated, and olfactoryepithelium, which comprises nerves which extend downwards through thecribiform plate CP from the olfactory bulb, whereas the anterior regionof the nasal airway is that region which is lined with squamousepithelium, which is not ciliated, and transitional epithelium, andextends to the skin-lined section at the nares of the nostril. Theolfactory epithelium extends on both the lateral and medial sides of thenasal airway, and typically extends downwards about 1.5 to 2.5 cm.

As illustrated in FIG. 1(b), the posterior region of the nasal airway isthe nasal region posterior of an imaginary vertical plane VERT1 which islocated at a position corresponding to one-quarter of the distancebetween the anterior nasal spine AnS, which is a pointed projection atthe anterior extremity of the intermaxillary suture, and the posteriornasal spine PnS, which is the sharp posterior extremity of the nasalcrest of the hard palate and represents the transition between the noseand the nasopharynx, which corresponds to a distance posterior of theanterior nasal spine AnS of between about 13 mm and about 14 mm[Rosenberger defines the distance between the anterior nasal spine AnSand the posterior nasal spine PnS as being 56 mm in eighteen year oldboys and 533 mm in eighteen year old girls]. As again illustrated inFIG. 1(b), the posterior nasal region is bounded posteriorly by animaginary vertical plane VERT2 which extends through the posterior nasalspine PnS.

The upper posterior region is the region above the inferior meatus IM,as illustrated in FIG. 1(b), and encompasses the middle turbinate, thesinus ostia in infundibulum (ostia to maxillary, frontal and ethmoidalsinuses), the olfactory region, and the upper branches of the trigeminalnerve, and is that region which includes veins which drain to the venoussinuses that surround the brain.

As further illustrated in FIG. 1(b), the upper region of the nasalairway is an upper segment of the nasal airway which is bounded by thecribiform plate CP and a horizontal plane HORIZ which is located at aposition corresponding to one-third of the distance between the nasalfloor NF of the nasal airway and the cribiform plate CP, whichcorresponds to a height of typically between about 13 and about 19 mmabove the nasal floor NF [Zacharek et al define the distance from thenasal floor NF to the cribiform plate CP as 46+/−4 mm].

The upper posterior region is thus that upper posterior region which isbounded by the above-defined vertical and horizontal planes VERT1,HORIZ.

There are many nasal conditions which require treatment. One suchcondition is nasal inflammation, specifically rhinitis, which can beallergic or non-allergic and is often associated with infection andprevents normal nasal function. By way of example, allergic andnon-allergic inflammation of the nasal airway can typically effectbetween 10 and 20% of the population, with nasal congestion of theerectile tissues of the nasal concha, lacrimation, secretion of waterymucus, sneezing and itching being the most common symptoms. As will beunderstood, nasal congestion impedes nasal breathing and promotes oralbreathing, leading to snoring and sleep disturbance. Other nasalconditions include nasal polyps which arise from the paranasal sinuses,hypertrophic adenoids, secretory otitis media, sinus disease and reducedolfaction.

In the treatment of certain nasal conditions, the topical administrationof medicaments is preferable, particularly where the nasal mucosa is theprime pathological pathway, such as in treating or relieving nasalcongestion.

Medica meats that are commonly topically delivered includedecongestants, anti-histamines, cromoglycates, steroids and antibiotics.At present, among the known anti-inflammatory pharmaceuticals, topicalsteroids have been shown to have an effect on nasal congestion. Topicaldecongestants have also been suggested for use in relieving nasalcongestion. The treatment of hypertrophic adenoids and chronic secretoryotitis media using topical decongestants, steroids and anti-microbialagents, although somewhat controversial, has also been proposed.Further, the topical administration of pharmaceuticals has been used totreat or at least relieve symptoms of inflammation in the anteriorregion of the nasopharynx, the paranasal sinuses and the auditory tubes.

Medicaments can also be systemically delivered through the nasalpathway, the nasal pathway offering a good administration route for thesystemic delivery of pharmaceuticals, such as hormones, for example,oxytocin and calcitonin, and analgetics, such as anti-migrainecompositions, as the high blood flow and large surface area of the nasaltissues advantageously provides for rapid systemic uptake.

In relation to systemic delivery, studies [Daley-Yates et al and Harriset al] have shown that significantly increased systemic bio-availabilityis achieved by delivery as a nasal spray as compared to drops.

Daley-Yates et al investigated the systemic bio-availability offluticasone propionate where delivered both as an aqueous spray and asnasal drops, and the bio-availability of the nasal spray formulation wasabout eight times higher than that of the nasal drop formulation. Theauthors of the this study have attributed this increasedbio-availability of the nasal spray formulation to the by-passing of thenose and an increased absorption from the gastro-intestinal (GI) tract,where the nose is by-passed by one or both of mucociliary clearance ofthe substance or sniffing the substance along the floor of the nose andsubsequent swallowing.

Harris et al investigated the intranasal administration of desmopressinas a nasal spray and as nasal drops, and the bio-availability of thenasal spray formulation was two to three times higher than that of thenasal drop formulation.

In line with these studies, the current understanding in the art is thatto achieve maximal absorption of substance to the systemic circulation,the substance should be delivered to as large a surface of the nasalcavity as possible.

The present inventors have now contrarily and surprisingly recognizedthat the delivery of substance to the anterior region of the nasalcavity and an anterior section of the posterior region of the nasalcavity, in particular the anterior third, and more particularly themidanterior third of the posterior region, predominantly influences thesystemic bio-availability of the substance, and, by controlling thedelivery of the substance to the anterior region of the nasal cavity andthe anterior section of the posterior region of the nasal cavity, a moreuniform and increased bio-availability can be achieved for a given doseof the substance. A particular problem of existing delivery regimes isthe significant variability in the systemic bio-availability, which thepresent inventors attribute to the significant variation in thedistribution of substance as delivered in subject to subject. Thepresent inventors have recognized that delivering the dose of substancein particular to the anterior region of the nasal cavity can provide adesired uniformity to the systemic bio-availability.

Nasal delivery is also expected to be advantageous for theadministration of medicaments requiring a rapid onset of action, forexample, analgetics, anti-emetics, insulin, anti-epileptics, sedativesand hypnotica, and also other pharmaceuticals, for example,cardio-vascular drugs. It is envisaged that nasal administration willprovide for a fast onset of action, at a rate similar to that ofinjection and at a rate much faster than that of oral administration.Indeed, for the treatment of many acute conditions, nasal administrationis advantageous over oral administration, since gastric stasis canfurther slow the onset of action following oral administration.

It is also expected that nasal delivery could provide an effectivedelivery route for the administration of proteins and peptides asproduced by modern biotechnological techniques. For such substances, themetabolism in the intestines and the first-pass-effect in the liverrepresent significant obstacles for reliable and cost-efficientdelivery.

Furthermore, it is expected that nasal delivery using the nasal deliverytechnique of the present invention will prove effective in the treatmentof many common neurological diseases, such as Alzheimer's, Parkinson's,psychiatric diseases and intracerebral infections, where not possibleusing existing techniques.

Also, it is expected that the nasal delivery technique of the presentinvention will allow for the effective delivery of vaccines.

Aside from the delivery of medicaments, the irrigation of the nasalmucosa with liquids, in particular saline solutions, is commonlypractised to remove particles and secretions, as well as to improve themucociliary activity of the nasal mucosa. These solutions can be used incombination with active pharmaceuticals.

For any kind of drug delivery, accurate and reliable dosing isessential, but it is of particular importance in relation to theadministration of potent drugs which have a narrow therapeutic window,drugs with potentially serious adverse effects and drugs for thetreatment of serious and life-threatening conditions. For someconditions, it is essential to individualize the dosage to theparticular situation, for example, in the case of diabetes mellitus. Asdiscussed hereinabove, a particular advantage of the present inventionis the reliability in the dosing. This is particularly the case even inthe event of a congested nose, such as with a cold or an allergy, asdelivery is to the anterior region, which is not congested, though theremay be some secretion.

WO-A-00/51672 discloses a delivery device for delivering substance, inparticular a medicament, in a bi-directional flow through the nasalcavities, that is, an air flow which passes into one nostril, around theposterior margin of the nasal septum and in the opposite direction outof the other nostril. This bi-directional air flow advantageously actsto stimulate the sensory nerves in the nasal mucosa, therebyconditioning the subject for the delivery and providing a morecomfortable delivery situation.

It is an aim of the present invention to provide improved nasal deliverydevices and nasal delivery methods, which in particular provide for oneor both of increased systemic bio-availability of the deliveredsubstance and improved dose-to-dose uniformity in the systemicbio-availability.

In one aspect the present invention provides a delivery device fordelivering a dose of substance for systemic uptake to a nasal cavity ofa subject, the delivery device comprising: a nosepiece unit forinsertion into a nasal cavity of a subject and comprising an outlet unitwhich includes at least one nozzle for delivering substance for systemicuptake substantially only to surfaces in one or both of the anteriorregion and an anterior section of the posterior region of the nasalcavity of the subject; and a substance supply unit which is operable todeliver a dose of substance to the at least one nozzle.

In another aspect the present invention provides a method of deliveringa dose of substance for systemic uptake to a nasal cavity of a subject,the method comprising the steps of: disposing a nosepiece unit in thenasal cavity of the subject, the nosepiece unit comprising at least onenozzle for delivering substance for systemic uptake to surfacessubstantially only in one or both of the anterior region and an anteriorsection of the posterior region of the nasal cavity of the subject; anddelivering a close of substance from a substance supply unit to the atleast one nozzle, such that the substance is delivered to surfacessubstantially only in one or both of the anterior region and an anteriorsection of the posterior region.

Preferred embodiments of the present invention will now be describedhereinbelow by way of example only with reference to the accompanyingdrawings, in which:

FIG. 1(a) schematically illustrates the anatomy of the upper respiratorytract of a human subject;

FIG. 1(b) illustrates the segmentation of a nasal cavity in accordancewith a preferred embodiment of the present invention;

FIG. 2 schematically illustrates a nasal delivery device in accordancewith a first embodiment of the present invention;

FIG. 3 schematically illustrates the delivery device of FIG. 2 insertedin a nasal cavity of a subject for operation;

FIG. 4 schematically illustrates the delivery device of FIG. 2 duringactuation;

FIG. 5 schematically illustrates the delivery device of FIG. 2 followingactuation;

FIG. 6 schematically illustrates a nasal delivery device in accordancewith a second embodiment of the present invention;

FIG. 7 schematically illustrates the delivery device of FIG. 6 insertedin a nasal cavity of a subject for operation;

FIG. 8 schematically illustrates the delivery device of FIG. 6 during afirst actuation phase in which a positive pressure is created in theanterior region by the exhalation breath;

FIG. 9 schematically illustrates the delivery device of FIG. 6 during asecond actuation phase in which the substance supply unit is actuated todeliver substance into the anterior region;

FIG. 10 schematically illustrates the delivery device of FIG. 6following actuation;

FIG. 11 schematically illustrates a nasal delivery device in accordancewith a third embodiment of the present invention;

FIG. 12 schematically illustrates the delivery device of FIG. 11inserted in a nasal cavity of a subject for operation;

FIG. 13 schematically illustrates the delivery device of FIG. 11 duringa first actuation phase in which a positive pressure is created in theanterior region by the exhalation breath;

FIG. 14 schematically illustrates the delivery device of FIG. 11 duringa second actuation phase in which the substance supply unit is actuatedto deliver substance into the anterior region;

FIG. 15 schematically illustrates the delivery device of FIG. 11following actuation;

FIG. 16 schematically illustrates a nasal delivery device in accordancewith a fourth embodiment of the present invention;

FIG. 17 schematically illustrates the delivery device of FIG. 15inserted in a nasal cavity of a subject for operation;

FIG. 18 schematically illustrates the delivery device of FIG. 16 duringactuation;

FIG. 19 schematically illustrates the delivery device of FIG. 16following actuation;

FIG. 20 schematically illustrates a nasal delivery device in accordancewith a fifth embodiment of the present invention;

FIG. 21 schematically illustrates the delivery device of FIG. 20inserted in a nasal cavity of a subject for operation;

FIG. 22 schematically illustrates the delivery device of FIG. 20 duringa first actuation phase in which the second nosepiece member of thenosepiece unit is inflated by the exhalation breath of the subject suchas to partition the nasal cavity;

FIG. 23 schematically illustrates the delivery device of FIG. 20 duringa second actuation phase in which the substance supply unit is actuatedto deliver substance into the anterior region;

FIG. 24 schematically illustrates the delivery device of FIG. 20following actuation;

FIG. 25 schematically illustrates a nasal delivery device in accordancewith a sixth embodiment of the present invention;

FIG. 26 schematically illustrates the delivery device of FIG. 25inserted in a nasal cavity of a subject for operation;

FIG. 27 schematically illustrates the delivery device of FIG. 25 duringactuation;

FIG. 28 schematically illustrates the delivery device of FIG. 25following actuation;

FIG. 29 schematically illustrates a nasal delivery device in accordancewith a seventh embodiment of the present invention;

FIG. 30 schematically illustrates the delivery device of FIG. 29inserted in a nasal cavity of a subject for operation;

FIG. 31 schematically illustrates the delivery device of FIG. 29 duringactuation;

FIG. 32 schematically illustrates the delivery device of FIG. 29following actuation;

FIG. 33 schematically illustrates a nasal delivery device in accordancewith an eighth embodiment of the present invention;

FIG. 34 schematically illustrates the delivery device of FIG. 33inserted in a nasal cavity of a subject for operation;

FIG. 35 schematically illustrates the delivery device of FIG. 33 duringactuation; and

FIG. 36 schematically illustrates the delivery device of FIG. 33following actuation.

FIGS. 2 to 5 illustrate a nasal delivery device in accordance with afirst embodiment of the present invention.

The delivery device comprises a housing 15, a nosepiece unit 17 forfitting in a nasal cavity of a subject through which substance isdelivered to the nasal cavity, and a substance supply unit 19 which isactuatable to deliver a metered dose of substance to the nosepiece unit17.

The nosepiece unit 17 comprises an outlet unit 21 which extends into thenasal cavity into which the nosepiece unit 17 is inserted, a firstnosepiece member 23, in this embodiment a frusto-conical element, whichis disposed to one, proximal end of the outlet unit 21 and is configuredto obstruct, in this embodiment close, the nostril into which thenosepiece unit 17 is inserted, a second nosepiece member 25 which isdisposed to the other, distal end of the outlet unit 21 and isconfigured to obstruct, in this embodiment close, the nasal cavity at aposition therealong, in this embodiment at a position correspondingsubstantially to the nasal valve, such as to partition the nasal cavityinto a first, anterior region 27 between the first and second nosepiecemembers 23, 25, which corresponds in volume to about one-third of thenasal cavity, and a second, posterior region 29, which corresponds involume to about the remaining two-thirds of the nasal cavity, asillustrated in FIG. 3.

The outlet unit 21 comprises a support member 31, in this embodiment anarrow, elongate element, to which the first and second nosepiecemembers 23, 25 are supported, and at least one nozzle 35, in thisembodiment a plurality of laterally-directed nozzles 35 a, b, disposedbetween the first and second nosepiece members 23, 25 for deliveringsubstance to the anterior region 27 of the nasal cavity.

In this embodiment the nozzles 35 a, b are configured to provide anaerosol spray. In an alternative embodiment the nozzles 35 a, b could beconfigured to deliver jets as columns of substance.

In this embodiment the second nosepiece member 25 comprises a resilientelement 37, here in the form of an annular skirt, which through itsresilience acts to expand to obstruct the nasal cavity in partitioningthe same. In an alternative embodiment the resilient element 37 couldtake the form of laterally-directed wings, which together act toobstruct the nasal cavity in partitioning the same.

In this embodiment the substance supply unit 19 comprises a mechanicaldelivery pump, in particular a liquid delivery pump or a powder deliverypump, which delivers metered doses of substance on actuation thereof.

In another alternative embodiment the substance supply unit 19 couldcomprise a dry powder delivery unit which delivers metered doses ofsubstance, as a dry powder, on actuation thereof.

In yet another alternative embodiment the substance supply unit 19 couldcomprise an aerosol canister which delivers metered volumes of apropellant, preferably a hydrofluoroalkane (HFA) propellant or the like,containing substance, either as a suspension or solution.

In yet another alternative embodiment the substance supply unit 19 couldcomprise a nebulizer which delivers metered doses of substance, as anaerosol spray, on actuation thereof.

In this embodiment the substance supply unit 19 is a multi-dose unit fordelivering a plurality of metered doses of substance. In anotherembodiment the substance supply unit 19 could be a single-dose unit fordelivering a single metered dose of substance.

In this embodiment the substance supply unit 19 is pre-primeable, hereby loading a resilient element, and includes an actuation mechanism 41which, when triggered, releases the resilient element and actuates thesubstance supply unit 19 to deliver a metered dose of substance throughthe nozzles 35 a, b of the outlet unit 21.

Operation of the delivery device will now be described hereinbelow withreference to FIGS. 3 to 5 of the accompanying drawings.

Referring to FIG. 3, the nosepiece unit 17 is first inserted into one ofthe nasal cavities of a subject until the first nosepiece member 23abuts the nares of the nostril, such as sealingly to engage theskin-lined anterior section of the anterior region of the nasal cavity.When inserted, the distal end of the outlet unit 21 extends about 2 cminto the nasal cavity of the subject, which corresponds in position tothat of the nasal valve, and the second nosepiece member 25 acts toobstruct the nasal cavity at that point such as to partition the nasalcavity.

Referring to FIG. 4, the subject then actuates the actuation mechanism41, in this embodiment manually, which acts to actuate the substancesupply unit 19 to deliver a metered dose of substance from the nozzles35 a, 35 b of the outlet unit 21.

The metered dose of substance, in this embodiment in the form of anaerosol spray, is confined to the anterior region 27 of the nasal cavityas defined between the first and second nosepiece members 23, 25. Asdescribed hereinabove, the present inventors have recognized that thesystemic uptake of substance as delivered via the nasal cavity is,contrary to current thinking, enhanced where delivered through theanterior region of the nasal cavity, and thus, by confining thedelivered dose of substance to the anterior region, an enhanced systemiceffect is obtained per unit dose of substance as compared to theconventional delivery of substances into the nasal cavity, such asgenerally by a nasal spray or nasal drops.

Following actuation, as illustrated in FIG. 5, the nosepiece unit 17 iswithdrawn from the nasal cavity of the subject.

In one embodiment, where the delivery device is a single-dose device, tidevice can be discarded.

In another embodiment, where the delivery device is a multi-dose device,the device is ready for further use following priming of the substancesupply unit 19. In a preferred embodiment, where the nosepiece unit 17is replaceable, the nosepiece unit 17 can be replaced with a newnosepiece unit 17.

FIGS. 6 to 10 illustrate a nasal delivery device in accordance with asecond embodiment of the present invention.

The delivery device of this embodiment is very similar to the deliverydevice of the above-described embodiment, and thus, in order to avoidunnecessary duplication of description, only the differences will bedescribed in detail.

The delivery device of this embodiment differs from that of theabove-described embodiment in that the support member 31 of the outletunit 21 includes a gas delivery port 45 which is disposed at a positionbetween the first and second nosepiece members 23, 25, and in furthercomprising a mouthpiece 47 which is fluidly connected to the gasdelivery port 45, such that, on exhalation into the mouthpiece 47, anair flow is delivered to the gas delivery port 45 which acts to developa pressure in the partitioned anterior region 27 as defined between thefirst and second nosepiece members 23, 25, which acts to expand theanterior region 27 and thereby promote the delivery of substancethereto.

Operation of the delivery device is illustrated in FIGS. 7 to 10 of theaccompanying drawings. The operation of the delivery device of thisembodiment is the same as that of the above-described embodiment, exceptin that the subject exhales through the mouthpiece 47 during actuationof the delivery device, in order to cause expansion of the partitionedanterior section.

In one alternative-embodiment the actuation mechanism 41 could be abreath-actuated mechanism, such that the actuation mechanism 41 acts toactuate the substance supply unit 19 on the generation of apredetermined pressure at the mouthpiece 47.

FIGS. 11 to 15 illustrate a nasal delivery device in accordance with athird embodiment of the present invention.

The delivery device of this embodiment is very similar to the deliverydevice of the above-described embodiment, and thus, in order to avoidunnecessary duplication of description, only the differences will bedescribed in detail.

The delivery device of this embodiment differs from that of theabove-described embodiment in that the support member 31 of the outletunit 21 includes a gas delivery port 45 which is disposed at a positionbetween the first and second nosepiece members 23, 25, and in furthercomprising a gas supply unit 49, in this embodiment a compressible bulb,which is fluidly connected to the gas delivery port 45 and actuatable todeliver an air flow to the gas delivery port 45 which acts to develop apressure in the partitioned anterior region 27 as defined between thefirst and second nosepiece members 23, 25, which acts to expand theanterior region 27 and thereby promote the delivery of substancethereto.

Operation of the delivery device is illustrated in FIGS. 12 to 15 of theaccompanying drawings. The operation of the delivery device of thisembodiment is the same as that of the above-described embodiment, exceptin that the subject actuates the gas supply unit 49, in this embodimentby compressing the bulb, during actuation of the delivery device, inorder to cause expansion of the partitioned anterior region 27.

FIGS. 16 to 19 illustrate a nasal delivery device in accordance with afourth embodiment of the present invention.

The delivery device comprises a housing 115, a nosepiece unit 117 forfitting in a nasal cavity of a subject through which substance isdelivered to the nasal cavity, and a substance supply unit 119 which isactuatable to deliver a metered dose of substance to the nosepiece unit117.

The nosepiece unit 117 comprises an outlet unit 121 which extends intothe nasal cavity into which the nosepiece unit 117 is inserted, and anosepiece member 123, in this embodiment a frusto-conical element, whichis disposed to one, proximal end of the outlet unit 121 and isconfigured to obstruct, in this embodiment close, the nostril into whichthe nosepiece unit 117 is inserted.

The outlet unit 121 comprises a support member 131, in this embodiment anarrow, elongate element, to which the nosepiece member 123 issupported, and at least one nozzle 135, in this embodiment a pluralityof laterally-directed nozzles 135 a, b, which is disposed such as todeliver substance substantially entirely to the anterior region 137 ofthe nasal cavity relative to the posterior region of the nasal cavity139. By configuring the at least one nozzle 135 such as to direct thesubstance laterally to the surfaces of the anterior region 137 of thenasal cavity, the substance is substantially entirely delivered to theanterior region 137 of the nasal cavity relative to the posterior region139 of the nasal cavity.

In this embodiment the nozzles 135 a, b are configured to provide anaerosol spray. In an alternative embodiment the nozzles 135 a, b couldbe configured to deliver jets as columns of substance.

In this embodiment the substance supply unit 119 comprises a mechanicaldelivery pump, in particular a liquid delivery pump or a powder deliverypump, which delivers metered doses of substance on actuation thereof.

In another alternative embodiment the substance supply unit 119 couldcomprise a dry powder delivery unit which delivers metered doses ofsubstance, as a dry powder, on actuation thereof.

In yet another alternative embodiment the substance supply unit 119could comprise an aerosol canister which delivers metered volumes of apropellant, preferably a hydrofluoroalkane (HFA) propellant or the like,containing substance, either as a suspension or solution.

In yet another alternative embodiment the substance supply unit 119could comprise a nebulizer which delivers metered doses of substance, asan aerosol spray, on actuation thereof.

In this embodiment the substance supply unit 119 is a multi-dose unitfor delivering a plurality of metered doses of substance. In anotherembodiment the substance supply unit 119 could be a single-dose unit fordelivering a single metered dose of substance.

In this embodiment the substance supply unit 119 is pre-primeable, hereby loading a resilient element, and includes an actuation mechanism 141which, when triggered, releases the resilient element and actuates thesubstance supply unit 119 to deliver a metered dose of substance throughthe nozzles 135 a, b of the outlet unit 121.

In another embodiment the substance supply unit 119 could be manuallyactuated, for example, by manually depressing or compressing anapplicator element.

Operation of the delivery device will now be described hereinbelow withreference to FIGS. 17 to 19 of the accompanying drawings.

Referring to FIG. 17, the nosepiece unit 117 is first inserted into oneof the nasal cavities of a subject until the nosepiece member 123 abutsthe nares of the nostril, such as sealingly to engage the skin-linedanterior section of the anterior region of the nasal cavity. Wheninserted, the distal end of the outlet unit 121 extends about 2 cm intothe nasal cavity of the subject, which corresponds in position to thatof the nasal valve.

Referring to FIG. 18, the subject then actuates the actuation mechanism141, in this embodiment manually, which acts to actuate the substancesupply unit 119 to deliver a metered dose of substance from the nozzles135 a, 135 b of the outlet unit 121.

The metered dose of substance, in this embodiment in the form of anaerosol spray, is confined to the anterior region 127 of the nasalcavity. As described hereinabove, the present inventors have recognizedthat the systemic uptake of substance as delivered via the nasal cavityis, contrary to current thinking, enhanced where delivered through theanterior region 127 of the nasal cavity, and thus, by confining thedelivered dose of substance to the anterior region 127, an enhancedsystemic effect is obtained per unit dose of substance as compared tothe conventional delivery of substances into the nasal cavity, such asgenerally by a nasal spray or nasal drops.

Following actuation, as illustrated in FIG. 19, the nosepiece unit 117is withdrawn from the nasal cavity of the subject.

In one embodiment, where the delivery device is a single-dose device,the device can be discarded.

In another embodiment, where the delivery device is a multi-dose device,the device is ready for further use following priming of the substancesup ply unit 119. In a preferred embodiment, where the nosepiece unit117 is replaceable, the nosepiece unit 117 can be replaced with a newnosepiece unit 117.

FIGS. 20 to 24 illustrate a nasal delivery device in accordance with afifth embodiment of the present invention.

The delivery device comprises a housing 215, a nosepiece unit 217 forfitting in a nasal cavity of a subject through which substance isdelivered to the nasal cavity, a substance supply unit 219 which isactuatable to deliver a metered dose of substance to the nosepiece unit117, and a mouthpiece unit 2220 through which the subject exhales.

The nosepiece unit 217 comprises an outlet unit 221 which extends intothe nasal cavity into which the nosepiece unit 117 is inserted, a firstnosepiece member 223, in this embodiment a frusto-conical element, whichis disposed to one, proximal end of the outlet unit 221 and isconfigured to obstruct, in this embodiment close, the nostril into whichthe nosepiece unit 217 is inserted, a second, expandable nosepiecemember 225 which is disposed to the other, distal end of the outlet unit221 and is configured, when expanded, to obstruct, in this embodimentclose, the nasal cavity at a position therealong, in this embodiment ata position corresponding substantially to the nasal valve, such as topartition the nasal cavity into a first, anterior region 227 between thefirst and second nosepiece members 223, 225, which corresponds in volumeto about one-third of the nasal cavity, and a second, posterior region229, which corresponds in volume to about the remaining two-thirds ofthe nasal cavity, as illustrated in FIG. 22.

The outlet unit 221 comprises a support member 231, in this embodiment anarrow, elongate element, to which the first and second nosepiecemembers 223, 225 are supported, and at least one nozzle 235, in thisembodiment a plurality of laterally-directed nozzles 235 a, b, disposedbetween the first and second nosepiece members 223, 225 for deliveringsubstance to the anterior region 227 of the nasal cavity.

In this embodiment the nozzles 235 a, b are configured to provide anaerosol spray. In an alternative embodiment the nozzles 235 a, b couldbe configured to deliver jets as columns of substance.

In this embodiment the second nosepiece member 225 comprises aninflatable member which is fluidly connected to the mouthpiece unit 220,such that, on exhalation by the subject through the mouthpiece unit 220,the second nosepiece member 225 is expanded to obstruct the nasal cavityin partitioning the same.

In this embodiment the substance supply unit 219 comprises a mechanicaldelivery pump, in particular a liquid delivery pump or a powder deliverypump, which delivers metered doses of substance on actuation thereof.

In another alternative embodiment the substance supply unit 219 couldcomprise a dry powder delivery unit which delivers metered doses ofsubstance, as a dry powder, on actuation thereof.

In yet another alternative embodiment the substance supply unit 219could comprise an aerosol canister which delivers metered volumes of apropellant, preferably a hydrofluoroalkane (HFA) propellant or the like,containing substance, either as a suspension or solution.

In yet another alternative embodiment the substance supply unit 219could comprise a nebulizer which delivers metered doses of substance, asan aerosol spray, on actuation thereof.

In this embodiment the substance supply unit 219 is a multi-dose unitfor delivering a plurality of metered doses of substance. In anotherembodiment the substance supply unit 219 could be a single-dose unit fordelivering a single metered dose of substance.

In this embodiment the substance supply unit 219 is pre-primeable, hereby loading a resilient element, and includes an actuation mechanism 241which, when triggered, releases the resilient element and actuates thesubstance supply unit 219 to deliver a metered dose of substance throughthe nozzles 235 a, b of the outlet unit 221.

In this embodiment the actuation mechanism 241 is a manually-actuatedunit, but in another embodiment could be a breath-actuated unit which isactuated in response to the generation of a predetermined pressure atthe mouthpiece unit 220, which is sufficient to provide for inflation ofthe second nosepiece member 225.

Operation of the delivery device will now be described hereinbelowreference to FIGS. 21 to 24 of the accompanying drawings.

Referring to FIG. 21, the nosepiece unit 217 is first inserted into oneof the nasal cavities of a subject until the first nosepiece member 223abuts the nares of the nostril, such as sealingly to engage theskin-lined anterior section of the anterior region of the nasal cavity.When inserted, the distal end of the outlet unit 221 extends about 2 cminto the nasal cavity of the subject, which corresponds in position tothat of the nasal valve.

Referring to FIG. 22, the subject then exhales through the mouthpieceunit 220, and the exhaled air flow acts to generate a pressure withinthe second nosepiece member 225, which is inflated such as to obstructthe nasal cavity and thereby partition the anterior and posteriorregions 227, 229 of the nasal cavity.

Referring to FIG. 23, the subject then actuates the actuation mechanism241, in this embodiment manually, which acts to actuate the substancesupply unit 219 to deliver a metered dose of substance from the nozzles235 a, 235 b of the outlet unit 221.

The metered dose of substance, in this embodiment in the form of anaerosol spray, is confined to the anterior region 227 of the nasalcavity as defined between the first and second nosepiece members 223,225. As described hereinabove, the present inventors have recognizedthat the systemic uptake of substance as delivered via the nasal cavityis, contrary to current thinking, enhanced where delivered through theanterior region 227 of the nasal cavity, and thus, by confining thedelivered dose of substance to the anterior region 227, an enhancedsystemic effect is obtained per unit dose of substance as compared tothe conventional delivery of substances into the nasal cavity, such asgenerally by a nasal spray or nasal drops.

Following actuation, as illustrated in FIG. 24, the nosepiece unit 217is withdrawn from the nasal cavity of the subject.

In one embodiment, where the delivery device is a single-dose device,the device can be discarded.

In another embodiment, where the delivery device is a multi-dose device,the device is ready for further use following priming of the substancesupply unit 219. In a preferred embodiment, where the nosepiece unit 217is replaceable, the nosepiece unit 217 can be replaced with a newnosepiece unit 217.

In one alternative embodiment the second nosepiece member 225 couldinstead be mechanically expanded, for example, by expandable armmembers.

FIGS. 25 to 28 illustrate a nasal delivery device in accordance with asixth embodiment of the present invention.

The delivery device comprises a housing 315, a nosepiece unit 317 forfitting in a nasal cavity of a subject through which substance isdelivered to the nasal cavity, a substance supply unit 319 which isactuatable to deliver metered doses of first and second substances tothe nosepiece unit 317, and a mouthpiece unit 320 through which thesubject exhales.

The nosepiece unit 317 comprises an outlet unit 321 which extends intothe nasal cavity into which the nosepiece unit 317 is inserted, a firstnosepiece member 323, in this embodiment a frusto-conical element, whichis disposed to one, proximal end of the outlet unit 321 and isconfigured to obstruct, in this embodiment close, the nostril into whichthe nosepiece unit 317 is inserted, a second nosepiece member 325 whichis disposed to the other, distal end of the outlet unit 321 and isconfigured to obstruct, in this embodiment close, the nasal cavity at aposition therealong, in this embodiment at a position correspondingsubstantially to the nasal valve, such as to partition the nasal cavityinto a first, anterior region 327 between the first and second nosepiecemembers 323, 325, which corresponds in volume to about one-third of thenasal cavity, and a second, posterior region 329, which corresponds involume to about the remaining two-thirds of the nasal cavity, asillustrated in FIG. 26.

The outlet unit 321 comprises a support member 331, in this embodiment anarrow, elongate element, to which the first and second nosepiecemembers 323, 325 are supported, at least one first, anterior nozzle 335,in this embodiment a plurality of laterally-directed anterior nozzles335 a, b, which is disposed between the first and second nosepiecemembers 323, 325 for delivering substance, in this embodiment substancefor systemic application, to the anterior region 327 of the nasalcavity, and at least one second, posterior nozzle 336, in thisembodiment a single, axially-directed nozzle, for delivering substance,in this embodiment substance for topical or CNS application, to theposterior region 329 of the nasal cavity.

In this embodiment the anterior nozzles 335 a, b are configured toprovide an aerosol spray. In an alternative embodiment the anteriornozzles 335 a, b could be configured to deliver jets as columns ofsubstance.

In this embodiment the posterior nozzle 336 is configured to provide anaerosol spray. In an alternative embodiment the posterior nozzle 335could be configured to deliver a jet as a column of substance.

In this embodiment the second nosepiece member 325 comprises a resilientelement 337, here in the form of an annular skirt, which through itsresilience acts to expand to obstruct the nasal cavity in partitioningthe same. In an alternative embodiment the resilient element 337 couldtake the form of laterally-directed wings, which together act toobstruct the nasal cavity in partitioning the same.

In this embodiment the substance supply unit 319 comprises a mechanicaldelivery pump, in particular a liquid delivery pump or a powder deliverypump, which delivers metered doses of first and second substances onactuation thereof.

In another alternative embodiment the substance supply unit 319 couldcomprise a dry powder delivery unit which delivers metered doses offirst and second substances, as dry powders, on actuation thereof.

In yet another alternative embodiment the substance supply unit 319could comprise an aerosol canister which delivers first and secondmetered volumes of a propellant, preferably a hydrofluoroalkane (HFA)propellant or the like, each containing substance, either as asuspension or solution.

In yet another alternative embodiment the substance supply unit 319could comprise a nebulizer which delivers metered doses of first andsecond substances, as aerosol sprays, on actuation thereof.

In this embodiment the substance supply unit 319 is a multi-dose unitfor delivering a plurality of metered doses of first and secondsubstances. In another embodiment the substance supply unit 319 could bea single-dose unit for delivering a single metered dose of first andsecond substances.

In this embodiment the substance supply unit 319 is pre-primeable, hereby loading a resilient element, and includes an actuation mechanism 341which, when triggered, releases the resilient element and actuates thesubstance supply unit 319 to deliver metered doses of first and secondsubstances through the respective ones of the anterior nozzles 335 a, band posterior nozzle 336 of the outlet unit 321.

Operation of the delivery device will now be described hereinbelow withreference to FIGS. 26 to 28 of the accompanying drawings.

Referring to FIG. 26, the nosepiece unit 317 is first inserted into oneof the nasal cavities of a subject until the first nosepiece member 323abuts the nares of the nostril, such as sealingly to engage theskin-lined anterior section of the anterior region of the nasal cavity.When inserted, the distal end of the outlet unit 321 extends about 2 cminto the nasal cavity of the subject, which corresponds in position tothat of the nasal valve, and the second nosepiece member 325 acts toobstruct the nasal cavity at that point such as to partition the nasalcavity.

Referring to FIG. 27, the subject then actuates the actuation mechanism341, in this embodiment manually, which acts to actuate the substancesupply unit 319 to deliver a metered dose of a first substance, in thisembodiment substance for systemic application, from the anterior nozzles335 a, 335 b of the outlet unit 321 and a metered dose of a secondsubstance, in this embodiment substance for topical or CNS application,from the posterior nozzle 336 of the outlet unit 321.

The metered dose of the first substance, in this embodiment in the formof an aerosol spray, is confined to the anterior region 327 of the nasalcavity as defined between the first and second nosepiece members 323,325. As described hereinabove, the present inventors have recognizedthat the systemic uptake of substance as delivered via the nasal cavityis, contrary to current thinking, enhanced where delivered through theanterior region 327 of the nasal cavity, and thus, by confining thedelivered dose of substance to the anterior region 327, an enhancedsystemic effect is obtained per unit dose of substance as compared tothe conventional delivery of substances into the nasal cavity, such asgenerally by a nasal spray or nasal drops.

Following actuation, as illustrated in FIG. 28, the nosepiece unit 317is withdrawn from the nasal cavity of the subject.

In one embodiment, where the delivery device is a single-dose device,the device can be discarded.

In another embodiment, where the delivery device is a multi-dose device,the device is ready for further use following priming of the substancesupply unit 319. In a preferred embodiment, where the nosepiece unit 317is replaceable, the nosepiece unit 317 can be replaced with a newnosepiece unit 317.

FIGS. 29 to 32 illustrate a nasal delivery device in accordance with aseventh embodiment of the present invention.

The delivery device comprises a housing 415, a nosepiece unit 417 forfitting in a nasal cavity of a subject through which substance isdelivered to the nasal cavity, a substance supply unit 419 which isactuatable to deliver a metered dose of substance to the nosepiece unit417, and a mouthpiece unit 420 through which the subject exhales.

The nosepiece unit 417 comprises a body unit 421 which comprises a firstnosepiece member 423, in this embodiment a frusto-conical element, whichis disposed at one, proximal end and is configured to obstruct, in thisembodiment close, the nostril into which the nosepiece unit 417 isinserted, and a second nosepiece member 425 which is disposed to theother, distal end and comprises a flexible, elongate element which issufficiently compliant extend into, and in one embodiment, through thenasal valve. The second nosepiece member 425 has a shape, size andsurface properties which enable the second nosepiece member 425comfortably to penetrate the nasal valve. In this embodiment, when thenosepiece unit 417 is fully inserted into a nasal cavity, the distal endof the second nosepiece member 425 extends from about 3 cm to about 5 cminto the nasal cavity.

The nosepiece unit 417 further comprises at least one, in thisembodiment a plurality of laterally-directed anterior nozzles 435 a, bwhich are configured such as to deliver substance, in this embodimentsubstance for systemic application, to surfaces within the anteriorregion of the nasal cavity, and at least one second, posterior nozzle435, in this embodiment a single, axially-directed nozzle, fordelivering the substance to surfaces in an anterior section of theposterior region of the nasal cavity, in this embodiment an anteriorthird of the posterior region, and a preferred embodiment a mid-anteriorthird of the posterior region, as illustrated in FIG. 1(b).

In this embodiment the anterior nozzles 435 a, b are configured toprovide an aerosol spray. In an alternative embodiment the anteriornozzles 435 a, b could be configured to deliver jets as columns ofsubstance.

In this embodiment the posterior nozzle 436 is configured to provide anaerosol spray. In an alternative embodiment the posterior nozzle 436could be configured to deliver a jet as a column of substance.

In this embodiment the substance supply unit 419 comprises a mechanicaldelivery pump, in particular a liquid delivery pump or a powder deliverypump, which delivers a metered dose of substance on actuation thereof.

In another alternative embodiment the substance supply unit 419 couldcomprise a dry powder delivery unit which delivers a metered dose ofsubstance, as a dry powder, on actuation thereof.

In yet another alternative embodiment the substance supply unit 419could comprise an aerosol canister which delivers a metered volume of apropellant, preferably a hydrofluoroalkane (HFA) propellant or the like,containing substance, either as a suspension or solution.

In yet another alternative embodiment the substance supply unit 419could comprise a nebulizer which delivers a metered dose of substance,as an aerosol spray, on actuation thereof.

In this embodiment the substance supply unit 419 is a multi-dose unitfor delivering a plurality of metered doses of substance. In anotherembodiment the substance supply unit 419 could be a single-dose unit fordelivering a single metered dose of substance.

In this embodiment the substance supply unit 419 is pre-primeable, hereby loading a resilient element, and includes an actuation mechanism 441which, when triggered, releases the resilient element and actuates thesubstance supply unit 419 to deliver a metered dose of substance throughthe anterior nozzles 435 a, b and the posterior nozzle 436. In thisembodiment the actuation mechanism 441 is breath actuated in response toexhalation by the subject through the mouthpiece unit 420.

Operation of the delivery device will now be described hereinbelow withreference to FIGS. 30 to 32 of the accompanying drawings.

Referring to FIG. 30, the nosepiece unit 417 is first inserted into oneof the nasal cavities of a subject until the first nosepiece member 423abuts the nares of the nostril, such as sealingly to engage theskin-lined anterior section of the anterior region of the nasal cavity,and the second nosepiece member 425 extends into the nasal valve.

Referring to FIG. 31, the subject then exhales through the mouthpieceunit 420, which exhalation triggers the actuation mechanism 441, whichin turn acts to actuate the substance supply unit 419 to deliver ametered dose of substance, in this embodiment substance for systemicapplication, from the anterior nozzles 435 a, 435 b and the posteriornozzle 435.

The substance as delivered from the anterior nozzles 435 a, b isdelivered to surfaces in the anterior region of the nasal cavity, andthe substance as delivered from the posterior nozzle 436 is delivered toan anterior section of the posterior region of the nasal cavity, in thisembodiment the anterior third of the posterior region of the nasalcavity, and more preferably substantially entirely to the mid-anteriorthird of the posterior region of the nasal cavity. As describedhereinabove, the present inventors have recognized that the systemicuptake of substance as delivered via the nasal cavity is, contrary tocurrent thinking, enhanced where delivered through the anterior regionof the nasal cavity and the anterior third of the posterior region ofthe nasal cavity, and thus, by confining the delivered dose of substanceto the anterior region and the anterior third of the posterior region ofthe nasal cavity, an enhanced systemic effect is obtained per unit doseof substance as compared to the conventional delivery of substances intothe nasal cavity, such as generally by a nasal spray or nasal drops.

Following actuation, as illustrated in FIG. 32, the nosepiece unit 417is withdrawn from the nasal cavity of the subject.

In one embodiment, where the delivery device is a single-dose device,the device can be discarded.

In another embodiment, where the delivery device is a multi-dose device,the device is ready for further use following priming of the substancesupply unit 419. In a preferred embodiment, where the nosepiece unit 417is replaceable, the nosepiece unit 417 can be replaced with a newnosepiece unit 417.

FIGS. 33 to 36 illustrate a nasal delivery device in accordance with aneighth embodiment of the present invention.

The delivery device comprises a housing 515, a nosepiece unit 517 forfitting in a nasal cavity of a subject through which substance isdelivered to the nasal cavity, and a substance supply unit 519 which isactuatable to deliver a metered dose of substance to the nosepiece unit517.

The nosepiece unit 517 comprises a body unit 521 which comprises a firstnosepiece member 523, in this embodiment a frusto-conical element, whichis disposed at one, proximal end and is configured to obstruct, in thisembodiment close, the nostril into which the nosepiece unit 517 isinserted, a second nosepiece member 525 which is disposed to the other,distal end and comprises a flexible, elongate element which issufficiently compliant to extend into, and in one embodiment, throughthe nasal valve, and a flow channel 527 which is fluidly connected to anactuation mechanism 541 of the substance supply unit 519, as will bedescribed in more detail hereinbelow.

The nosepiece unit 517 further comprises at least one, in thisembodiment a plurality of laterally-directed anterior nozzles 535 a, bwhich are configured such as to deliver substance, in this embodimentsubstance for systemic application, to surfaces within the anteriorregion of the nasal cavity, and at least one second, posterior nozzle536, in this embodiment a single, axially-directed nozzle, fordelivering the substance to surfaces in an anterior section of theposterior region of the nasal cavity, in this embodiment an anteriorthird of the posterior region, and a preferred embodiment a mid-anteriorthird of the posterior region, as illustrated in FIG. 1(b).

In this embodiment the anterior nozzles 535 a, b are configured toprovide n aerosol spray. In an alternative embodiment the anteriornozzles 535 a, b could be configured to deliver jets as columns ofsubstance.

In this embodiment the posterior nozzle 536 is configured to provide anaerosol spray. In an alternative embodiment the posterior nozzle 536could be configured to deliver a jet as a column of substance.

In this embodiment the substance supply unit 519 comprises a mechanicaldelivery pump, in particular a liquid delivery pump or a powder deliverypump, which delivers a metered dose of substance on actuation thereof.

In another alternative embodiment the substance supply unit 519 couldcomprise a dry powder delivery unit which delivers a metered dose ofsubstance, as a dry powder, on actuation thereof.

In yet another alternative embodiment the substance supply unit 519could comprise an aerosol canister which delivers a metered volume of apropellant, preferably a hydrofluoroalkane (HFA) propellant or the like,containing substance, either as a suspension or solution.

In yet another alternative embodiment the substance supply unit 519could comprise a nebulizer which delivers a metered dose of substance,as an aerosol spray, on actuation thereof.

In this embodiment the substance supply unit 519 is a multi-dose unitfor delivering a plurality of metered doses of substance. In anotherembodiment the substance supply unit 519 could be a single-dose unit fordelivering a single metered dose of substance.

In this embodiment the substance supply unit 519 is pre-primeable, hereby loading a resilient element, and includes an actuation mechanism 541which, when triggered, releases the resilient element and actuates thesubstance supply unit 519 to deliver a metered dose of substance throughthe anterior nozzles 535 a, b and the posterior nozzle 536. In thisembodiment the actuation mechanism 541 is breath actuated in response tonasal exhalation by the subject, which nasal exhalation acts to generatea positive pressure in the nasal cavity, which is fluidly connected tothe actuation mechanism 541 by the flow channel 527 of the nosepieceunit 517. The generation of a positive pressure in the nasal cavity alsoadvantageously provides for expansion of the nasal cavity, whichfacilitates deposition on the surfaces within the nasal cavity.

Operation of the delivery device will now be described hereinbelow withreference to FIGS. 34 to 36 of the accompanying drawings.

Referring to FIG. 34, the nosepiece unit 517 is first inserted into oneof the nasal cavities of a subject until the first nosepiece member 523abuts the nares of the nostril, such as sealingly to engage theskin-lined anterior section of the anterior region of the nasal cavity,and the second nosepiece member 525 extends into the nasal valve.

Referring to FIG. 35, the subject then exhales, or at least attempts toexhale through the nasal cavity, which nasal exhalation triggers theactuation mechanism 441, which in turn acts to actuate the substancesupply unit 519 to deliver a metered dose of substance, in thisembodiment substance for systemic application, from the anterior nozzles535 a, 535 b and the posterior nozzle 536.

The substance as delivered from the anterior nozzles 535 a, b isdelivered to surfaces in the anterior region of the nasal cavity, andthe substance as delivered from the posterior nozzle 536 is delivered toan anterior section of the posterior region of the nasal cavity, in thisembodiment the anterior third of the posterior region of the nasalcavity, and more preferably substantially to the mid-anterior third ofthe posterior region of the nasal cavity. As described hereinabove, thepresent inventors have recognized that the systemic uptake of substanceas delivered via the nasal cavity is, contrary to current thinking,enhanced where delivered through the anterior region of the nasal cavityand the anterior third of the posterior region of the nasal cavity, andthus, by confining the delivered dose of substance to the anteriorregion and the anterior third of the posterior region of the nasalcavity, an enhanced systemic effect is obtained per unit dose ofsubstance as compared to the conventional delivery of substances intothe nasal cavity, such as generally by a nasal spray or nasal drops.

Following actuation, as illustrated in FIG. 36, the nosepiece unit 517is withdrawn from the nasal cavity of the subject.

In one embodiment, where the delivery device is a single-dose device,the device can be discarded.

In another embodiment, where the delivery device is a multi-dose device,the device is ready for further use following priming of the substancesupply unit 519. In a preferred embodiment, where the nosepiece unit 417is replaceable, the nosepiece unit 517 can be replaced with a newnosepiece unit 517.

Finally, it will be understood that the present invention has beendescribed in its preferred embodiments and can be modified in manydifferent ways without departing from the scope of the invention asdefined by the appended claims.

For example, in one embodiment the substance could be formulated such asto hinder mucociliary clearance, as would occur from the ciliatedmucosal surfaces in the posterior region of the nasal cavity, and alsoprevent gravitational flow of the substance and dripping out of thesubstance from the nasal cavity. Typically, the formulation could haveadhesive properties, for example, as a thixotropic formulation, and inone embodiment could be formulated in the manner of a gel.

In another embodiment the substance supply units 19, 119, 219, 319, 419,519 of the above-described embodiments could be configured to deliver acombination of liquid and powdered substances.

REFERENCES

-   -   1. Cole, P. The Respiratory Role of the Upper Airway, Mosby,        1992, pages 7 and 8.    -   2. Daley-Yates, P T et al, Systemic bioavailability of        fluticasone propionate administered as nasal drops and aqueous        nasal spray formulations, Br J Clin Pharmacol, January 2001,        51(1), pages 103 to 105.    -   3. Harris A S et al, Intranasal administration of peptides:        nasal deposition, biological response and absorption of        desmopressin, J Pharm Sci, November 1985, 75(11), pages 1085 to        1088.    -   4. Rosenberger, H, Growth and Development of the        Naso-Respiratory Area in Childhood, PhD Thesis, Laboratory of        Anatomy, School of Medicine, Western Reserve University,        Presented to the Annual Meeting of the American Laryngological,        Rhinological and Otological Society, Charleston, S.C., USA,        1934.    -   5. Zacharek, M A et al, Sagittal and Coronal Dimensions of the        Ethmoid Roof: A Radioanatomic Study, Am J Rhinol 2005, Vol 19,        pages 348 to 352.

The invention claimed is:
 1. A substance delivery device for deliveringa first substance and a second substance to a nasal cavity of a subjectfor systemic uptake, the delivery device comprising: a nosepiece forinsertion into the nasal cavity of the subject, the nosepiece includingan outlet unit comprising: a first nozzle for delivering the firstsubstance; a second nozzle for delivering the second substance; and aposterior nosepiece member configured to obstruct the nasal cavity andpartition the nasal cavity into an anterior region and a posteriorregion, such that the first substance is delivered from the first nozzleto surfaces only in the anterior region and the second substance isdelivered from the second nozzle to surfaces only in an anterior portionof the posterior region; and a substance supply unit configured todeliver the first substance to the first nozzle and the second substanceto the second nozzle.
 2. The delivery device of claim 1, wherein thesubstance supply unit is breath actuated on exhalation by the subject.3. The delivery device of claim 1, wherein the substance supply unit isbreath actuated on nasal exhalation by the subject.
 4. The deliverydevice of claim 1, wherein the substance supply unit is manuallyactuated.
 5. The delivery device of claim 1, wherein the outlet unitcomprises two first nozzles, each of the two first nozzles beingarranged so as to direct the first substance to a lateral surface withinthe anterior region of the nasal cavity.
 6. The delivery device of claim1, wherein the first nozzle is substantially laterally directed so as todirect the first substance to a lateral surface within the anteriorregion of the nasal cavity.
 7. The delivery device of claim 1, whereinthe first nozzle is configured to deliver a liquid.
 8. The deliverydevice of claim 1, wherein the first nozzle is configured to deliver apowder.
 9. The delivery device of claim 1, wherein the posterior regioncomprises the region of the nasal cavity posterior of the nasal valve.10. The delivery device of claim 1, wherein the posterior nosepiecemember is configured to close the nasal valve of the subject.
 11. Thedelivery device of claim 1, further comprising: a mouthpiece throughwhich the subject exhales to cause closure of an oropharyngeal velum ofthe subject.
 12. The delivery device of claim 1, wherein the secondnozzle is substantially laterally directed so as to direct the secondsubstance to a lateral surface within the anterior portion of theposterior region of the nasal cavity.
 13. A method of delivering a firstsubstance and a second substance to a nasal cavity of a subject forsystemic uptake, the method comprising: inserting a nosepiece into thenasal cavity of the subject, the nosepiece including an outlet unithaving: a first nozzle for delivering the first substance, a secondnozzle for delivering the second substance, and a posterior nosepiecemember configured to obstruct the nasal cavity and partition the nasalcavity into an anterior region and a posterior region; causing the firstsubstance to be delivered from the first nozzle to surfaces in theanterior region; and causing the second substance to be delivered fromthe second nozzle to surfaces in an anterior portion of the posteriorregion.
 14. The method of claim 13, wherein the first nozzle issubstantially laterally directed so as to direct the first substance toa lateral surface within the anterior region of the nasal cavity. 15.The method of claim 13, wherein the first nozzle is configured todeliver a liquid.
 16. The method of claim 13, wherein the first nozzleis configured to deliver a powder.
 17. The method of claim 13, whereinthe posterior region comprises the region of the nasal cavity posteriorof the nasal valve.
 18. The method of claim 13, wherein the posteriornosepiece member is configured to close the nasal valve of the subject.19. The method of claim 13, further comprising: inserting a mouthpieceinto a mouth of the subject through which the subject exhales to causeclosure of an oropharyngeal velum of the subject.
 20. The method ofclaim 13, wherein the second nozzle is substantially laterally directedso as to direct the second substance to a lateral surface within theanterior portion of the posterior region of the nasal cavity.